Discovery of 2-iminobenzimidazoles as a new class of trypanothione reductase inhibitor by high-throughput screening

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 5, 2007, Pages 1422-1427

  Holloway, Georgina A ^a   Baell, Jonathan B ^a   Fairlamb, Alan H ^b   Novello, Patrizia M ^a   Parisot, John P ^a   Richardson, John ^b   Watson, Keith G ^a   Street, Ian P ^a  

^a WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH   (Australia)

^b WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

Author keywords

High throughput screening; Iminobenzimidazoles; Medicinal chemistry; Tropical diseases; Trypanosomiasis therapeutics; Trypanothione reductase inhibitors

Indexed keywords

2 IMINOBENZIMIDAZOLE DERIVATIVE; BENZIMIDAZOLE DERIVATIVE; ENZYME INHIBITOR; TRYPANOTHIONE REDUCTASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; CONTROLLED STUDY; CYTOTOXICITY; DRUG ACTIVITY; ENZYME INHIBITION; HIGH THROUGHPUT SCREENING; IC 50; MAMMAL CELL; NONHUMAN; STRUCTURE ACTIVITY RELATION; TRYPANOSOMA RHODESIENSE;

ANIMALS; BENZIMIDAZOLES; BINDING, COMPETITIVE; CELL SURVIVAL; COMBINATORIAL CHEMISTRY TECHNIQUES; DRUG EVALUATION, PRECLINICAL; HUMANS; INHIBITORY CONCENTRATION 50; NADH, NADPH OXIDOREDUCTASES; STRUCTURE-ACTIVITY RELATIONSHIP; TRYPANOSOMA BRUCEI RHODESIENSE;

MAMMALIA; TRYPANOSOMA BRUCEI RHODESIENSE;

EID: 33846955093     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.11.090     Document Type: Article

References (34)

1. www.who.int/tdr/diseases/default.htm.
2. Fairlamb A.H. Trends Parasitol. 19 (2003) 488
3. Paulino M., Iribarne F., Dubin M., Aguilera-Morales S., Tapia O., and Stoppani A.O.M. Mini-Rev. Med. Chem. 5 (2005) 499
4. Sundar S., More D.K., Singh M.K., Singh V.P., Sharma S., Makharia A., Kumar P.C.K., and Murray H.W. Clin. Infect. Dis. 31 (2000) 1104
5. Croft S.L., Sundar S., and Fairlamb A.H. Clin. Microbiol. Rev. 19 (2006) 111
6. Fairlamb A.H., Blackburn P., Ulrich P., Chait B.T., and Cerami A. Science 227 (1985) 1485
7. Dumas C., Ouellette M., Tovar J., Cunningham M.L., Fairlamb A.H., Tamar S., Olivier M., and Papadopoulou B. EMBO J. 16 (1997) 2590
8. Krieger S., Schwarz W., Ariyanayagam M.R., Fairlamb A.H., Krauth-Siegel R.L., and Clayton C. Mol. Microbiol. 35 (2000) 542
9. Schmidt A., and Krauth-Siegel R. Curr. Top. Med. Chem. 2 (2002) 1239
10. Tovar J., Wilkinson S., Mottram J.C., and Fairlamb A.H. Mol. Microbiol. 29 (1998) 653
11. Marsh I.R., and Bradley M. Eur. J. Biochem. 243 (1997) 690
12. Hunter W.N., Bailey S., Habash J., Harrop S.J., Helliwell J.R., Aboagye-Kwarteng T., Smith K., and Fairlamb A.H. J. Mol. Biol. 227 (1992) 322
13. Krauth-Siegel R.L., Meiering S.K., and Schmidt H. Biol. Chem. 384 (2003) 539
14. Lipinski C.A., Lombardo F., Dominy B.W., and Feeney P.J. Adv. Drug Delivery Rev. 23 (1997) 3
15. Oprea T.I., Davis A.M., Teague S.J., and Leeson P.D. J. Chem. Inf. Comput. Sci 41 (2001) 1308
16. Hamilton C.J., Saravanamuthu A., Eggleston I.M., and Fairlamb A.H. Biochem. J. 369 (2003) 529
17. 2 (6 μM), DTNB (100 μM), compound (25 μM) and NADPH (150 μM).
18. Zhang J.-H., Chung T.D.Y., and Oldenburg K.R. J. Biomol. Screen. 4 (1999) 67
19. Saravanamuthu A., Vickers T.J., Bond C.S., Peterson M.R., Hunter W.N., and Fairlamb A.H. J. Biol. Chem. 279 (2004) 29493
20. Chan C., Yin H., Garforth J., McKie J.H., Jaouhari R., Speers P., Douglas K.T., Rock P.J., Yardley V., Croft S.L., and Fairlamb A.H. J. Med. Chem. 41 (1998) 148
21. Garforth J., Yin H., McKie J.H., Douglas K.T., and Fairlamb A.H. J. Enzym. Inhib. 12 (1997) 161
22. The identity of synthesized compounds was confirmed by NMR and MS and their purity was determined to be >95%.
23. Da Settimo A., Da Settimo F., Marini A.M., Primofiore G., Salerno S., Viola G., Da Via L., and Magno S.M. Eur. J. Med. Chem. 33 (1998) 685
24. Morishita S., Saito T., Hirai Y., Shoji M., Mishima Y., and Kawakami M. J. Med. Chem. 31 (1988) 1205
25. Monosubstitution:. Shinkai S., Harada A., Ishikawa Y., Manabe O., and Yoneda F. J. Chem. Soc., Perkin. Trans. 2 (1982) 125
26. Second substitution with RBr:. Ursini A., et al. J. Med. Chem. 43 (2000) 3596
27. Second substitution with ROTs:. Lakatsoh S.A., Luzikov Y.N., and Preobrazhenskaya M.N. Tetrahedron 61 (2005) 2017
28. Rivas F.M., Giessert A.J., and Diver S.T. J. Org. Chem. 67 (2002) 1708
29. The pKa of the iminoguanidyl core was calculated using ACD software to be 11.1 and would be protonated under the assay conditions, but dropped to 2.5 upon acylation, which would not be protonated under the assay conditions.
30. i values.
31. Parveen S., Khan M.O.F., Austin S.E., Croft S.L., Yardley V., Rock P., and Douglas K.T. J. Med. Chem. 48 (2005) 8087
32. 2 (62.5 μM), DTNB (100 μM), compound (25 μM) and NADPH (150 μM).
33. Bi X., Lopez C., Bacchi C.J., Rattendi D., and Woster P.M. Bioorg. Med. Chem. Lett. 16 (2006) 3229
34. Stewart M.L., Boussard C., Brun R., Gilbert I.H., and Barrett M.P. Antimicrob. Agents Chemotherap. 49 (2005) 5169